Signal transducer and activator of transcription 3 (“STAT3”) is a member of the STAT family of transcription factors that relate signals from extracellular signaling protein receptors on the plasma membrane directly to the nucleus. See e.g., Bromberg et al., The Role of STATs in Transcriptional Control and their Impact on Cellular Function, Oncogene, 19: 2468-2473 (2000).
STAT3 has been shown to be constitutively activated in cancer including, but not limited to, cancers of the brain, head, neck, breast, prostate, lung, ovary, pancreas, leukemia, multiple myeloma, and lymphoma. See e.g., Song et al., STAT Signaling in Head and Neck Cancer, Oncogene, 19: 2489-2495 (2000); Garcia et al., Constitutive Activation of STAT3 in Fibroblasts Transformed By Diverse Oncoproteins and in Breast Carcinoma Cells, Cell Growth Duff., 812: 1267-76 (1997); Schaefer et al., Constitutive Activation of STAT3 in Brain Tumors: Localization to Tumor Endothelial Cells and Activation by the Endothelial Tyrosine Kinase Receptor (VEGFR-2), Oncogene, 21: 2058-2065 (2002); Dhir et al., STAT3 Activation in Prostatic Carcinomas, Prostate, 51: 241-246 (2002); Seki et al., STAT3 and MAPK in Human Lung Cancer Tissues and Suppression Of Oncogenic Growth by JAB and Dominant Negative STAT3, Int. J. Oncology, 24: 931-934 (2004); Huang et al., Constitutive Activation of STAT3 Oncogene Product in Human Ovarian Carcinoma Cells, Gynecol. Oncol., 79: 67-73 (2000); Scholz et al., Activated Signal Transducer and Activator of Transcription 3 (STAT3) Supports the Malignant Phenotype of Human Pancreatic Cancer, Gastroenterology, 125: 891-905 (2003); Benekti et al., Signal Transducer and Activator of Transcription Proteins in Leukemias, Blood, 101: 2940-2954 (2003); Weber-Nordt et al., Constitutive Activation of STAT Proteins in Primary Lymphoid and Myeloid Leukemia Cells and in Epstein-Barr Virus (EBV)-Related Lymphoma Cell Lines, Blood, 88: 809-816 (1996); Bowman et al., STATs In Oncogenesis, Oncogene, 19: 2474-2488 (2000); Yu, H.; Jove, R. The STATs of cancer—new molecular targets come of age, Nat. Rev. Cancer, 4: 97-105, (2004).
Small molecules have been developed that inhibit the STAT3 pathway; however, there remains a need for compounds that selectivity inhibit the STAT3 pathway and not the STAT1 pathway and which exhibit anti-proliferative activity. Furthermore, there is a need for compounds that demonstrate improved, potency, solubility and/or stability. The present invention satisfies these needs.